The invention relates to antimicrobial cationic polyamines, and more specifically, to cationic modified polyethylenimines for antimicrobial applications.
The rapid emergence of antibiotic-resistant infections, which makes infectious diseases increasingly difficult to control with the existing classes of antibiotics, has caused a great concern in the healthcare field and provided an impetus for continued antimicrobial development.
Multicellular organisms naturally defend themselves against infections from opportunistic pathogens using host defense peptides. These antimicrobial peptides were effective against a broad spectrum of pathogens, such as Gram-positive and Gram-negative bacteria, fungi and protozoa. The cationic amphiphilic peptides enter the lipid domain of bacterial cell membrane and disintegrate the cell membrane. However, the clinical application of antimicrobial peptides is limited because the peptides are generally sensitive to enzymatic degradation, are toxic, and are expensive for large-scale production.
Polyethylenimines (PEIs) are polyamines, and are commercially available in a broad range of molecular weights. The PEIs are formed as either linear (LPEI) or branched (BPEI) macromolecules. PEIs have found many applications in products, such as detergents, adhesives, water treatment agents, and cosmetics. Due to their ability to enter a cell through the cell membrane, PEIs have been utilized as drug carriers in biomedical applications. Polycationic PEIs can mediate gene transfer into mammalian cells in vitro and in vivo as a complex with DNA.
PEIs have also displayed antimicrobial activity after chemical modification. For example, quaternized BPEI (QPEI) showed antimicrobial ability against Escherichia coli (E. coli) at low concentrations (Gao, et al., J. Biomaterial Science, Polymer Edition, 2007, 18, 531-544). As another example, BPEI quaternized with long alkyl groups exhibited some degree of antimicrobial activity against E. coli (Pasquier, et al., Biomacromolecules, 2007, 8, 2874-2882). As another example, LPEI was grafted with long alkyl chains to produce a series of hydrophobically modified water insoluble LPEI derivatives, which were painted on a glass slide using an organic solvent (Fortune, et al., J. Drug Delivery, 2011, Article ID 204058). The coatings killed E. coli and Staphylococcus aureus (S. aureus) effectively.
Recently, the antimicrobial properties of linear and branched PEIs of various molecular weights was studied (K. Gibney, Thesis, University of Michigan, 2009). LPEIs generally showed higher activity against E. coli and S. aureus than BPEIs, but were more hemolytic to human red blood cells (human RBCs). Moreover, compared to water-miscible BPEI, LPEI is not easily dissolved in water even at room temperature. To prepare LPEI aqueous solution, a small volume of ethanol can be added to facilitate LPEI dissolution.
An ongoing need exists for broad spectrum antimicrobial agents that are non-hemolytic.